tbuckley/cabot-search huggingface dataset:
P04.09.B UNCOVERING GROUP 4 MEDULLOBLASTOMA THROUGH HUMAN CEREBELLARORGANOIDS
Authors: G Leva, C Lago, C Ballabio, M Anderle, E Miele, L Tiberi
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Central nervous system tumors are the second most prevalent cancers in the pediatric population and among them, medulloblastoma (MB) is the most common and malignant one. MB is divided in four major subgroups: WNT, SHH, group 3 and group 4. Despite this classification, recent studies have highlighted many genetic features shared between the last two subgroups making the patients’ stratification less distinct. Particularly, group 4 MB is the most common subtype, but the least understood. Single-cell transcriptomics studies identified Unipolar Brush Cells (UBCs) as putative cell of origin of group 4 MB subtype. Despite G4 MB being the most common subtype, there is still a paucity of models. In this scenario, my aim is to implement and adapt the cerebellar organoids experimental design already established by Ballabio et al. for G3 MB towards G4 MB modeling. MATERIAL AND METHODS We generated cerebellar organoids starting from human pluripotent stem cells. Thanks to the PiggyBac/transposon system and the CRISPR/CAS9 technology we electroporated organoids achieving putative genes’ overexpression and downregulation. Organoids were live-imaged weekly checking for proliferative cells clusters formation and, after having reached the tumorigenic phenotype, they were engrafted in nude mice. The classification of the tumor obtained is based on DNA methylation analysis. Immunostainings were performed on mice cerebella and organoids to identify their cell types. RESULTS Because of the aggressiveness and the lack of knowledge of G4 MB, we focused on the development of a cerebellar organoids-based model genetically modified to achieve the tumorigenic phenotype. We studied the best time window in which Tbr2+ (UBCs marker) cells are most present in organoids, deciding to electroporate them at day 70 of differentiation. Based on RNA-seq data of G4 MB patients, organoids were modified with different combinations of genetic alterations. Interestingly, some of them showed the appearance of hyperproliferating engineered cells forming clusters. However, only the co-overexpression of MYCN and Otx2 developed a tumor when engrafted in nude mice. The following DNA methylation analysis attributed the tumor to G3 MB. Hence the need to clone the hTbr2 promoter to guide the expression of oncogenes through a Cre-LoxP system in the UBCs neural progenitors. We confirmed the new promoter specificity through an immunofluorescent quantitative analysis and then performed the genetic screening mentioned above to compare the outcome with our previous results. CONCLUSION Despite the timing, the mutational screening performed did not show the expected outcome: since G3 and G4 have common genetic features, we can’t rely on the strong ubiquitous non-specific promoter (CAG). Hence, we suppose that the hTbr2 promoter-guided gene expression could be the promising way toward G4 MB modeling.
OS09.4.A RANO 2.0: UPDATE TO THE RESPONSE ASSESSMENT IN NEURO-ONCOLOGY (RANO) CRITERIA FOR HIGH- AND LOW-GRADE GLIOMAS IN ADULTS
Authors: P Wen, M Van Den Bent, G Youssef, T Cloughesy, B Ellingson, M Weller, E Galanis, D Barboriak, J DeGroot, M Gilbert, R Huang, A Lassman, M Mehta, A Molinaro, M Preusser, R Rahman, L Shankar, R Stupp, J Sul, J Villanueva-Meyer, W Wick, D Macdonald, D Reardon, M Vogelbaum, S Chang
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The Response Assessment in Neuro-Oncology (RANO) criteria for high-grade gliomas (RANO-HGG) and low-grade gliomas (RANO-LGG) were developed to improve reliability of response assessment in glioma trials. Over time some limitations of these criteria were identified, and uncertainty emerged regarding integrating features of the modified RANO (mRANO) or the immunotherapy RANO (iRANO) criteria. MATERIAL AND METHODS Informed by data from a cohort of glioblastoma patients and other evaluations of RANO criteria that allowed evaluation of features of the different criteria, the RANO working group developed updates to the RANO criteria (RANO 2.0). RESULTS Based on the 2021 WHO classification of gliomas, we recommend a standard set of criteria for both high and low-grade gliomas, to be used for all trials regardless of the treatment modalities being evaluated. In the newly diagnosed setting, the post-radiotherapy MRI, rather than the post-surgical MRI, will be used as the baseline for future comparison. Since the incidence of pseudoprogression is high in the 12 weeks following radiotherapy, continuation of treatment and confirmation of progression during this period with a repeat MRI, or histopathologic evidence of unequivocal recurrent tumor, is required to define tumor progression. However, confirmation scans are not mandatory after this period nor for recurrent tumors. For treatments with a high likelihood of pseudoprogression, mandatory confirmation of progression with a repeat MRI is highly recommended. The primary measurement remains the maximum cross-sectional area of tumor (2-dimensional) but volumetric measurements are an option. For IDH-wildtype glioblastoma, the non-enhancing disease will no longer be evaluated. In IDH-mutated tumors with a significant non-enhancing component, clinical trials may require evaluating both the enhancing and non-enhancing tumor components for response assessment. CONCLUSION These criteria represent a work in progress that will hopefully improve the assessment of response in glioma trials. Future updates will incorporate novel developments, advanced imaging techniques, and endpoints as they become validated.
PL02.4.A SHARED DECISION-MAKING IN NEUROSURGICAL CONSULTATIONS WITH NEWLY DIAGNOSED BRAIN TUMOR PATIENTS: A THEMATIC ANALYSIS OF PATIENT INVOLVEMENT
Authors: I J M Bras, M M Sitskoorn, M C W Joosen, I J M Vugt, A P Y Hoogendoorn, G J M Rutten, K Gehring
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND In shared decision-making (SDM) the patient serves as the expert on his or her own life and the health care professional serves as the medical expert. However, many SDM instruments that employ observer coding schemes primarily focus on information provision, and less on patient involvement. The items that are included on patient involvement are as follows: 1) introducing SDM to the patient, 2) providing personalized information and 3) discussing patient’s views, values and situation. These items may mark the presence of patient involvement and will be taken as a starting-point for this study, yet they do not provide information on how these items are discussed as part of the SDM process. The aim of this study is to illustrate the involvement of newly diagnosed brain tumor patients in SDM by analysing the decision-making process during neurosurgical consultations and identifying sub-themes related to patient involvement. MATERIAL AND METHODS This study employed a codebook thematic analysis to identify the sub-themes concerning aspects of patient involvement in the neurosurgical decision-making process. The first consultation between newly diagnosed glioma or meningioma patients and their neurosurgeons were audio-recorded, transcribed and coded. The study followed a recursive design continuing with analysis until data saturation was reached. RESULTS Saturation was reached after analysing 11 consultations. We identified 13 sub-themes within the three main themes, and we will support our findings with direct quotes from the consultations during the conference presentation. Theme 1 was comprised of the sub-themes inviting the patients to participate, presenting treatment options, inquiring about symptoms and daily life, asking patients about treatment preference and room for questions. Questions about patients’ personal circumstances are often asked near the end of a consultation, when the decision regarding treatment has already been made. Theme 2 was comprised of the sub-themes personalizing information, personalizing aspects of treatment and personalizing treatment recommendations. There are examples of neurosurgeons integrating information provided by the patient to personalize the decision-making process. Theme 3 was comprised of the sub-themes interference of disease, daily life, family and requested information. These sub-themes show what patients (spontaneously) share about their lives. CONCLUSION We illustrated how brain tumor patients contribute to the SDM process, what information patients and their decision-partners provide and how this information is integrated in the decision-making process during neurosurgical consultations. Our findings may provide handholds to further improve patient involvement and personalization of the decision-making process.
P02.07.A IMMUNOLOGICAL AND EPIGENETIC FEATURES OF RADIATION NECROSIS IN GLIOBLASTOMA PATIENTS
Authors: I C Mildenberger, V Perez-Montessoro, L Bunse, F Sahm, M Ratliff, F A Giordano, M Platten
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Radiation necrosis is a rare but highly relevant complication after radiotherapy in glioblastoma patients. Immunological and epigenetic features of these delayed tissue changes are not yet understood and no reliable biomarker to identify patients at risk of developing radiation necrosis is available. AIM To assess methylation patterns, T cell receptor repertoires and immune cell infiltration in patients with radiation necrosis and identify possible predictive epigenetic and immunological features. METHODS 405 glioblastoma patients who underwent tumor resection between 2008 and 2018 were retrospectively screened for histology-proven or MR-spectroscopy/FET-PET-diagnosed radiation necrosis (RN). After identifying patients with RN, a control cohort matched for age, sex and MGMT-status was established. For both cohorts, epigenetic profiles of primary tumor tissues were assessed via DNA methylation arrays. Immunohistochemistry was performed for CD3, CD8, CD68 and CD163. For patients with histology-proven RN, additional TCRß-bulk sequencing of DNA extracted from FFPE tissue of primary tumor and RN was performed. RESULTS 14/405 (3.5%) patients were identified with RN. The MGMT-promotor was hypermethylated in 50% of patients. The most prominent methylation subclasses of primary tumor tissue of patients in the RN cohort were GBM RTK I and GBM RTK II (5/8). None of these tumors was classified as GBM MES, which in contrast was the most prominent subclass in the control cohort (4/8). T cell infiltration and microglia/macrophage density did not differ between RN cohort and control cohort (CD3: 15.04 vs 20.28 counts/ROI, p= 0.55; CD8: 7.32 vs 8.3, p= 0.82; CD68: 7.42 vs 11.86, p=0.13; CD163: 14.29 vs 16.2, p= 0.73). In total, 1762 unique productive TCRß sequences were identified, overall productive clonality was low (0.2, range 0.06-0.4). A clonal expansion of specific TCRs from primary tumor to RN was identified in 2 patients. A more clonal repertoire in RN was observed in 50% of patients. 2 TCRß sequences were shared between 2 different patients, no sequences were shared between more than 2 patients. CONCLUSION Our data indicate that the methylation subclasses RTK I and RTK II may constitute a risk factor for RN whereas a MES subclass may be protective. Immune cell profiles in primary tumors of GBM patients that develop radiation necrosis during their treatment do not differ from primary tumors of control patients. TCR repertoire shows an overall low abundance of TCRs with polyclonal repertoires, but clonal expansion could be detected in a subset of patients, suggesting antigen-specific T cell responses to RN. Further analysis and validation of these findings in a larger cohort is ongoing.
P18.05.A THE GROWTH PATTERN OF MENINGIOMA CELLS IN CELL CULTURE UNDER DIFFERENT CONDITIONS
Authors: S Linsler, A Moroldo, J Oertel, S Urbschat
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Cell cultures is an established method in tumor research. Thereby, the growth rate is important for the results. Depending on the experimental and clinical setting, the used tissue is exposed to different conditions. Interestingely, the different cell and tissue conditions are not well reported yet. Although, it is likely that the different conditions influence the growth pattern of cell cultures in primary cell lines. Here, the authors present their experimental analysis of cell culture of primary meningioma cells after different initial tissue conditions. MATERIAL AND METHODS From June to December 2022 ten primary human meningiomas were collected after surgery at the Neurosurgical Department of the Saarland University. Primary cell cultures (Passage 0 = P0) were set up on the day of surgery and one day postoperatively. These tissues were kept overnight in nutrient solution in the refrigerator. They were splitted in two P1 cultures (Passage 1). The termination of the cell culture occured when the flasks were fully grown. One P1 culture was used for Fluorescence in situ hybridization. The other one was frozen on liquid nitrogen. The latter is thawed after six months and cultivated again. Additionally, swab preparations were made for Fluorescence in situ hybridization. The frozen tissue of these meningiomas was also used for further cell cultures. RESULTS Eight of ten cases (80%) of the meningioma cell cultures (from the day of surgery and one day postoperatively) have grown. In one case only the cell culture from the day of surgery has grown and in another one there were only single cells, no growth out of this tissue. The cell cultures prepared from frozen tissues have not shown any culture growth. There were not any significant differences between the growth of the cell culture from the day of surgery and of the cell culture from one day after surgery. The results of the Fluorescence in situ hybridization have shown a loss of 1p in one meningioma, a loss of 22q in three meningiomas, a loss of 1p and 22q in three meningiomas and a normal chromosome set in three tumours. Further, there were not any differences between the evaluation of swab preparations and drop preparations. Until now, six out of six thawed cell cultures of the first three meningiomas can be cultured again after six months in liquid nitrogen. CONCLUSION It has been shown that the growth pattern of meningioma cell cultures is independent of the set up at the same day or one day after surgery if there are enough living cells in the tissue. On the other hand, meningioma cell culturing of frozen tissues is not possible in the same setting.
P03.04.B EFFICACY OF NEOADJUVANT STEREOTACTIC RADIOSURGERY IN SOLID CANCER BRAIN METASTASES: A SYSTEMATIC REVIEW AND METANALYSIS
Authors: F Gagliardi, P De Domenico, S Snider, M Nizzola, P Mortini
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Neoadjuvant stereotactic radiosurgery (NaSRS) is a novel strategy for brain metastasis (BMs) management, promising to achieve lower rates of toxicity, leptomeningeal progression, and high percentage of local control. MATERIAL AND METHODS An extensive systematic literature review and meta-analysis of proportions were performed. A total of 8 papers were eligible for final analysis after searching MEDLINE via PubMed, Web-of-science, Cochrane Wiley, and Embase databases. RESULTS A total of 551 patients undergoing NaSRS to treat 583 lesions were included. Median age was 57.7 [56.5-61.1] years, with a median tumor volume of 9.1 [8.3-14.4] cc. The most frequent histology was non-small cell lung cancer (40.7%), followed by breast (20.5%), and melanoma (15.6%). Most of the lesions had a supratentorial location (77.6%). Treatment parameters were homogenous across the studies and showed a median dose of 16 [14.9-20.5] Gy at 80% isodose.Surgery was performed after a median of 1 [1-2] day and achieved gross-total extent in 92.4% of cases. Median follow-up was 12.9 [9.9-18.9] months.Pooled proportion of patients showed an overall mortality rate of 50% (CI 37-63; I2=87%), local failure of 15% (CI 12-20%; I2=12.1%) and a rate of distant brain failure of 42% (CI 35-49%; I2=55.3%). The median local progression-free survival (PFS) was 10.4 months, while median survival without distant failure was 8 months.Rate of radionecrosis (RN) and leptomeningeal dissemination (LMD) were 4% respectively. Median overall survival (OS) was 14.4 months. CONCLUSION Existing data suggest that NaSRS achieves good local control on BMs with relatively lower dose than adjuvant treatment and low incidence of RN and other complications. These results need to be confirmed by larger studies with higher level of evidence to address formal comparisons with other regimens.
OS12.5.A HIGH-GRADE GLIOMAS OCCURRING IN TEENAGERS AND YOUNG ADULT PATIENTS COMPRISE NOVEL MOLECULAR SUBGROUPS
Authors: M T Clarke, R Pereira, A Mackay, Y Grabovska, A Clarke, J Nicoll, J Procter, A Moore, J Schagen, L Walker, F Roncaroli, O Ogunbigi, T Jacques, L Marshall, F Carceller, Z Reisz, S Al-Sarraj, M Vinci, K Kurian, H Ng, S Brandner, C Jones
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND High-grade gliomas (HGG) arise in any central nervous system location, in adults and children, with a poor prognosis. HGGs in teenagers and young adults (TYA) are understudied; this project aimed to characterise these tumours and identify potential therapeutic targets. MATERIAL AND METHODS HGG samples (n=195, FFPE/FF, 13-30 years) were collected from national/international collaborators, excluding well-characterised entities (histone/IDH-mutant). DNA methylation profiling (Illumina EPIC BeadArrays, brain tumour classifier (MNP v12.5 R package), n=195) classified cases against a reference cohort. Calibrated scores guided workflows to characterise mutational landscapes including RNA-based ArcherDx fusion panel (n=112), whole exome sequencing (n=84), and histological reviews in parallel. Well-characterised entities (n=50, including IDH-mutant tumours (n=18), PXA (n=12)) were excluded. RESULTS Of the cases scoring &amp;gt;0.6, 64% classified as paediatric-type subgroups (pedHGG_RTK1A/B/C (30%), pedHGG_MYCN (10%), pedHGG_A/B (7%), pedHGG_RTK2A (6%)). 29% classified as subgroups more frequently seen in adults (GBM_MES (12%), GBM_RTK1/2 (3%)). 54% classified with a score &amp;lt;0.6. 38% cases were assigned to novel, recently identified, poorly-characterised subgroups with distinct methylation profiles and molecular features (HGG_B, HGG_E, ANTCON, GBM_CBM). Frequency comparisons to publicly available methylation data showed GBM_MES_ATYP tumours are TYA age-specific, in contrast to adult age-specific GBM_MES_TYP. Copy number profiling identified frequent changes across the cohort, including chromosomal gains (chr1q (54%), chr2 (22%), chr7 (41%)) and losses (chr10 (40%), chr13 (64%)). Focal amplifications included PDGFRA (12%), CDK4 (7%), MYCN/ID2 (3%), MYC (2%) and EGFR (0.7%) and the most common focal deletion was CDKN2A/p16 (12%). The most frequent glioma-associated somatic variants included TP53, PDGFRA, EGFR, and NF1. BCOR alterations were enriched compared to adult and paediatric reference cohorts. 10% cases showed a hypermutator phenotype, enriched in HGG_E. CDK4 amplifications were recurrent in GBM_RTK1 and GBM_CBM. Histology showed variable cytological and architectural features within novel subgroups. CONCLUSION TYA HGG comprise novel subgroups with distinct methylation profiles and molecular characteristics, representing opportunities to refine future treatment.
P16.02.B DIAGNOSTIC ACCURACY OF CSF LIQUID BIOPSY AND MRI FOR LEPTOMENINGEAL METASTASES IN SOLID CANCERS: A META-ANALYSIS
Authors: Y Nakasu, S Deguchi, S Nakasu, M Yamazaki, A Notsu, K Mitsuya, N Hayashi
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Leptomeningeal metastasis (LM) is a life-threatening and quickly advancing complication in patients with solid cancer. Reliable diagnosis is challenging. CSF cytology remains the standard diagnostic test for LM, though the sensitivity has been reportedly at un-satisfactory levels ranging 40 to 60% in the literature. We evaluated the diagnostic accuracy of CSF liquid biopsy and advanced magnetic resonance imaging (MRI) for detecting LM in patients with solid cancers. MATERIAL AND METHODS A systematic search was conducted to identify all published diagnostic accuracy studies on CSF liquid biopsies and MRI on electronic databases with registration for PROSPERO. Articles were selected based on pre-defined criteria following the PRISMA 2020 statement. Assessment of Risk of Bias (ROB) was based on QUADAS 2. RESULTS The search yielded 3790 citations to screen between January 2000 to March 2022. Ten studies with 668 patients were included in the final analysis: seven studies of circulating tumor cells (CTC), five studies of MRI, and two studies of cell-free tumor DNA (ctDNA). The pooled prevalence of LM was 50.9% (340/668). The sensitivity was calculated presenting synthetic results as follows: CTC, 87.0% [95% CI: 77.9-92.6]; ctDNA, 97.9% [19.3-100]; MRI 59.4% [60.7-76.9]; cytology, 71.9% [54.7-82.9].The synthesized specificity was as follows: CTC, 93.8% [86.9-97.2]; ctDNA, 89.0% [25.3-99.5]; MRI 97.6% [77.3-99.8]. The diagnostic odds ratio was 100.6 (29.38-344.09) for CTC and 93.3 (88.42-1034.05) for MRI. ROB assessment showed high risk sources in domains of patient selection and index test. CONCLUSION his study showed a better sensitivity of CSF cytology than the reports in the literature. Novel CSF liquid biopsies had sufficient sensitivities, and advanced MRI had a high specificity. Cytology and the new diagnostic methods are complementary and may offer early diagnosis and improved diagnostic accuracy for LM in patients with solid cancers. Further research is required to specify the threshold values and to construct standards of biomarker-driven and less invasive approach for individual cancers, and they would facilitate clinical trials for LM in the era of targeted therapy.